Platelet-activating factor (PAF) is a phospholipid with diverse physiologic actions. One important action is the induction of polymorphonuclear leukocyte (PMN) adhesion and priming of PMNs for secretion in response to subsequent stimuli. PAF is degraded by a specific phospholipase designed PAF acetylhydrolase. We hypothesize that intracellular PAF acetylhydrolase suppresses inflammation and protects cells against oxidative damage. We will test this hypothesis by isolating a mouse genomic clone for PAF acetylhydrolase and disrupting the gene by homologous recombination in ES cells. The functional consequences of the disruption will be transgenic animals by measuring responses to a variety of inflammatory stimuli. We predict that transgenic animals will respond to stimuli with more severe and prolonged inflammatory reactions in several different tissues.